Lung cancer remains the leading cause of cancer mortality in the US and throughout the world (Jemal A, et al. (2011) Global cancer statistics. CA Cancer J Clin 61 2): 69-90), with most patients presenting with advanced stage disease. The five-year survival rate for advanced stage non-small cell lung cancer (NSCLC) remains below 10%, necessitating the need for novel therapeutic strategies against advanced disease (Heist R S, Engelman J A (2012) SnapShot: non-small cell lung cancer. Cancer Cell 21 3): 448 e2). A significant clinical hurdle to reduce mortality in NSCLC is the propensity for tumor cell invasiveness and metastasis. Despite pharmacological advances for NSCLC, current treatments have limited efficacy in metastatic disease, and the majority of patients succumb to the overwhelming tumor burden resulting from tumor spread. Even molecularly targeted therapeutics such as the epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) fail due to tumor resistance, followed by disease progression. Two targets associated with NSCLC metastasis are the hepatocyte growth factor receptor (HGFR/c-Met) and fibroblast growth factor-inducible 14 (Fn14).
c-Met and its cognate ligand, hepatocyte growth factor (HGF), have been associated with tumor progression and metastasis in many solid tumor types (Stella G M, Benvenuti S, Comoglio P M (2010) Targeting the MET oncogene in cancer and metastases. Expert Opin Investig Drugs 19 11): 1381-94). Within adenocarcinomas, the most common subtype of NSCLC, the protein expression of c-Met was detected in ˜30% of cases and c-Met gene amplification was seen in 10% of cases (Tsuta K, et al. (2012) c-MET/phospho-MET protein expression and MET gene copy number in non-small cell lung carcinomas. J Thorac Oncol 7 2): 331-9). Increased c-Met activity has been observed to occur secondary to oncogenic activation of k-Ras (Yang Y, et al. (2008) A selective small molecule inhibitor of c-Met, PHA-665752, reverses lung premalignancy induced by mutant K-ras. Mol Cancer Ther 7 4): 952-60), while gene amplification of c-Met is often a mechanism of resistance to EGFR-TKIs (Bean J, et al. (2007) MET amplification occurs with or without T790M mutations in EGFR mutant lung tumors with acquired resistance to gefitinib or erlotinib. Proc Natl Acad Sci USA 104 52): 20932-7).
Furthermore, the expression of c-Met was more common in poorly differentiated adenocarcinomas compared to well-differentiated tumors (Tsuta K, et al. (2012) c-MET/phospho-MET protein expression and MET gene copy number in non-small cell lung carcinomas. J Thorac Oncol 7 2): 331-9). Among all types of NSCLC, c-Met expression was also significantly correlated with brain metastasis (Benedettini E, et al. (2010) Met activation in non-small cell lung cancer is associated with de novo resistance to EGFR inhibitors and the development of brain metastasis. Am J Pathol 177 1): 415-23). Ectopic expression of both HGF and c-Met in the NSCLC cell line H460 induced spontaneous metastasis to distant organs (Navab R, et al. (2009) Co-overexpression of Met and hepatocyte growth factor promotes systemic metastasis in NCI-H460 non-small cell lung carcinoma cells. Neoplasia 11 12): 1292-300). Thus, an improved understanding of HGF/c-Met signaling may offer novel therapeutic opportunities against advanced metastatic NSCLC.
The TNF-like weak inducer of apoptosis (TWEAK)-Fn14 signaling axis has been implicated in tumor growth, cell survival, and tumor invasion. Increased expression of Fn14 has been observed in a number of solid tumors, including hepatocellular carcinoma (Feng S L, et al. (2000) The Fn14 immediate-early response gene is induced during liver regeneration and highly expressed in both human and murine hepatocellular carcinomas. Am J Pathol 156 4): 1253-61), glioblastoma (GB) (Tran N L, et al. (2003) The human Fn14 receptor gene is up-regulated in migrating glioma cells in vitro and overexpressed in advanced glial tumors. Am J Pathol 162 4): 1313-21; Tran N L, et al. (2006) Increased fibroblast growth factor-inducible 14 expression levels promote glioma cell invasion via Rac1 and nuclear factor-kappaB and correlate with poor patient outcome. Cancer Res 66 19): 9535-42), esophageal adenocarcinoma (Watts G S, et al. (2007) Identification of Fn14/TWEAK receptor as a potential therapeutic target in esophageal adenocarcinoma. Int J Cancer 121 10): 2132-9), and HER2+ breast cancer (Willis A L, et al. (2008) The fibroblast growth factor-inducible 14 receptor is highly expressed in HER2-positive breast tumors and regulates breast cancer cell invasive capacity. Mol Cancer Res 6 5): 725-34). Fn14 is also highly expressed in NSCLC (Whitsett T G, et al. (2012) Elevated expression of Fn14 in non-small cell lung cancer correlates with activated EGFR and promotes tumor cell migration and invasion. Am J Pathol 181 1): 111-20), and Fn14 expression significantly correlates with activated EGFR. Additionally, Fn14 expression was maintained at a high level in NSCLC cells resistant to EGFR-TKIs. In GB, Fn14 signaling modulated cell survival through regulation of NF-κB, Bcl-xL, and Bcl-2 expression and Akt2 activation (Fortin S P, et al. (2009) Tumor necrosis factor-like weak inducer of apoptosis stimulation of glioma cell survival is dependent on Akt2 function. Mol Cancer Res 7 11): 1871-81; Tran N L, et al. (2005) The tumor necrosis factor-like weak inducer of apoptosis (TWEAK)-fibroblast growth factor-inducible 14 (Fn14) signaling system regulates glioma cell survival via NFkappaB pathway activation and BCL-XL/BCL-W expression. J Biol Chem 280 5): 3483-92). Fn14 signaling also promoted glioma and breast cell invasion through activation of Rac1 and NF-κB (Tran N L, et al. (2006) Increased fibroblast growth factor-inducible 14 expression levels promote glioma cell invasion via Rac1 and nuclear factor-kappaB and correlate with poor patient outcome. Cancer Res 66 19): 9535-42; Willis A L, et al. (2008) The fibroblast growth factor-inducible 14 receptor is highly expressed in HER2-positive breast tumors and regulates breast cancer cell invasive capacity. Mol Cancer Res 6 5): 725-34).
In NSCLC, Fn14 signals to induce cell migration and invasion in vitro, and ectopic expression of Fn14 enhanced metastasis in vivo (Whitsett T G, et al. (2012) Elevated expression of Fn14 in non-small cell lung cancer correlates with activated EGFR and promotes tumor cell migration and invasion. Am J Pathol 181 1): 111-20). Thus, Fn14 may play a critical role in cancer cell invasion and metastasis and represent a potential therapeutic vulnerability in advanced stage NSCLC. Efforts to directly target the TWEAK/Fn14 signaling pathway are currently under investigation (Zhou H, et al. (2011) Development and characterization of a potent immunoconjugate targeting the Fn14 receptor on solid tumor cells. Mol Cancer Ther 10 7): 1276-88), and clinical trials are ongoing (http://clinicaltrials.gov/ct2/show/NCT01383733).
In view of the aforementioned, there is a need to further understand Fn14 and c-Met expression and whether these markers are correlated in NSCLC tumors (e.g., primary tumors) and/or metastatic lesions. There is also a need to understand c-Met signaling and if c-Met signaling enhances Fn14 protein expression. Moreover, there is further a need to understand the potential impact of depletion of Fn14 on c-Met driven cell migration and invasion to understand the overall role of c-Met and Fn14 in an invasive phenotype of NSCLC.